Tumor production of endothelin-1 (ET-1) mediates new bone formation associated with osteoblastic metastases through the endothelin A receptor (ETA). However, the mechanisms by which this occurs and the role of ET-1 in normal bone remodeling is unknown, and will be the topic of this investigation. Aim 1: ET-1 stimulates new bone growth but whether this occurs by increased proliferation of osteoprogenitor cells, enhanced differentiation to mature osteoblasts or by inhibition of osteoblast apoptosis will be determined. Aim 2: The transactivation of the epidermal growth factor receptor by ET-1 will be tested to establish 1) if this is an important signaling pathway responsible for stimulating osteoblast activity and 2) whether estradiol modulates this effect. Aim 3: The roles of Wnt5a and Dickkopf homolog 1 autocrine signaling, Beta-catenin and the calcium-sensitive signaling pathways in ET-1 stimulation of osteoblast activity will be tested. Aim 4: The Cre-loxP system was utilized to make an osteoblast-specific knockout mouse with a targeted deletion of ETA. Since sex steroids modulate the effects of ETA blockade, eugonadal and castrated mice will be analyzed for gross anatomic and histologic bone developmental abnormalities. [unreadable] [unreadable]